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Causes of Natural Variation in Fitness: Evidence from Studies Of Correction EVOLUTION Correction for “Causes of natural variation in fitness: Evidence from studies of Drosophila populations,” by Brian Charlesworth, which appeared in issue 6, February 10, 2015, of Proc Natl Acad Sci USA (112:1662–1669; first published January 8, 2015; 10.1073/ pnas.1423275112). The authors note that on page 1666, right column, first full paragraph, line 6, “an estimate of t of 0.044” should instead appear as “an estimate of t over both classes of mutation of 0.0073.” The authors also note that on page 1666, right column, fourth full paragraph, line 3, “although even this is likely to be a sub- stantial underestimate” should instead appear as “although the overall value is likely to be somewhat less than 0.01.” www.pnas.org/cgi/doi/10.1073/pnas.1502053112 CORRECTION www.pnas.org PNAS | March 3, 2015 | vol. 112 | no. 9 | E1049 Downloaded by guest on September 30, 2021 Causes of natural variation in fitness: Evidence from INAUGURAL ARTICLE studies of Drosophila populations Brian Charlesworth1 Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2013. Contributed by Brian Charlesworth, December 12, 2014 (sent for review September 18, 2014; reviewed by James Fry and David Houle) DNA sequencing has revealed high levels of variability within most quantitative genetics, respectively. The first approach sheds light species. Statistical methods based on population genetics theory on the general nature of the fitness effects of the DNA sequence have been applied to the resulting data and suggest that most variants found in natural populations, but says little about how mutations affecting functionally important sequences are deleteri- these fitness effects are caused. The second tells us how much ous but subject to very weak selection. Quantitative genetic studies genetic variability exists for fitness traits, the rate at which it arise have provided information on the extent of genetic variation within by mutation and something about the type of selection involved, populations in traits related to fitness and the rate at which but is silent about the nature of the underlying sequence variants. variability in these traits arises by mutation. This paper attempts Surprisingly little attention has been paid to integrating these to combine the available information from applications of the two two lines of inquiry, except for ref. 7. I largely confine myself to approaches to populations of the fruitfly Drosophila in order to results from studies of the fruitfly Drosophila, because this has estimate some important parameters of genetic variation, using been the most useful model organism for investigating these a simple population genetics model of mutational effects on fitness problems, especially by quantitative genetics methods. Current components. Analyses based on this model suggest the existence of information derived from population genomics studies will first be a class of mutations with much larger fitness effects than those reviewed, followed by an analysis of the results of quantitative inferred from sequence variability and that contribute most of the standing variation in fitness within a population caused by the input genetics experiments on both mutational and standing variation. I EVOLUTION of mildly deleterious mutations. However, deleterious mutations show that the quantitative genetics results can only be explained if explain only part of this standing variation, and other processes there is a significant input of new mutations with much larger such as balancing selection appear to make a large contribution to effects on fitness than those inferred from population genomics. genetic variation in fitness components in Drosophila. There also appears to be too much genetic variation in fitness components in natural populations to be explained purely by mutation selection balance, so that additional processes such as mutation | selection | genetic variability | Drosophila balancing selection must make an important contribution. Advances in DNA sequencing methods have enabled geneti- Population Genomics Analyses cists to measure the amount of genetic variability in natural DNA sequencing has revolutionized studies of three aspects of populations at the most basic level: the frequencies of variants variability: the mutational processes that generate new variants, in nucleotide sequences. This achievement has ended one com- the amount of variation between individuals within a species, and ponent of a debate on the extent and causes of genetic variability the extent of between-species differences. Analyses of the evolu- that was initiated in the 1950s by Hermann Muller and Theodosius tionary forces affecting the fates of DNA sequence variants need Dobzhansky (1, 2); we now know that DNA sequences are highly to use all three types of information. Here I discuss evidence about variable within the populations of most species (3). It has, however, been much harder to provide a definitive answer to the other Significance component of this debate, which concerns the nature and intensity of the evolutionary forces that influence the frequencies of genetic The extent and causes of genetic variation have been debated variants within populations (1, 2, 4, 5). Are these variants mostly for 60 y. This paper synthesizes evidence from studies of DNA selectively neutral (6), with the fates of new mutations determined sequence variability in Drosophila and from experiments on by random fluctuations in their frequencies (genetic drift)? Is se- the quantitative genetics of fitness components. Two major lection on variants that affect fitness mostly purifying, so that conclusions emerge. First, a class of mutations with relatively mutations with harmful effects are rapidly removed from the large fitness effects contributes importantly to both the overall population (1)? Or do many loci have variants maintained by effect of new mutations on fitness components and to stand- balancing selection (2)? What fraction of newly arisen variants ing variation. These mutations are not detected in analyses of cause higher fitness and are in the process of spreading through the sequence variability. Second, a large fraction of variability in population and replacing their alternatives? How strong is the se- fitness components must be maintained by selection rather lection acting on nonneutral variants, and how much variation in than reflecting deleterious variants introduced by mutation. fitness among individuals within populations is contributed by such These results imply that both approaches to the study of nat- variants? Does the existence of wide variation in fitness among ural variation are needed to obtain a complete understanding individuals imply a genetic load that threatens the survival of the of its causes. species (1)? These questions are very broad, and this paper deals only with Author contributions: B.C. designed research, performed research, analyzed data, and one aspect of them. It focuses on the question of how recent wrote the paper. inferences concerning the strength of purifying selection, derived Reviewers: J.F., University of Rochester; D.H., Florida State University. from genome-wide surveys of DNA sequence variability, can be The author declares no conflict of interest. connected with the results of statistical studies of genetic variation 1Email: [email protected]. in components of Darwinian fitness such as viability and fertility. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. I will refer to these two approaches as population genomics and 1073/pnas.1423275112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1423275112 PNAS Early Edition | 1of8 the rate at which selectively deleterious mutations arise in the and deletions (12, 16, 17). However, this estimate is subject to genome as a whole (the “deleterious mutation rate”), and the considerable uncertainty, because inbred lines with independent extent to which sequence variants affect fitness. origins differ in their mutation rates (12, 16, 17). The mutation rate for a typical outbred fly is therefore not known with much Mutation Rates and Levels of Selective Constraint. It is now possible confidence. A value of 0.5 will be used in the discussions below, to estimate the rate of mutation to nucleotide sequence variants but should be regarded as provisional. Large-scale experiments for the genome as a whole, by determining the rate at which using pairs of outbred individuals and their offspring are needed these arise de novo in families or in breeding experiments, as to obtain a more reliable estimate (19). described below. We can also estimate the extent to which puri- fying selection acts to eliminate deleterious mutations that arise in Estimating the Fitness Effects of Mutations from Polymorphism Data. different compartments of the genome (coding sequences, intron The availability of DNA sequences from multiple individuals of sequences, and intergenic sequences), as indicated by their relative the same species, for sets of many genes or for whole genomes, degrees of sequence divergence from a related species (8). The has motivated the development of methods for inferring the type proportion of sites that are conserved for a given class of se- of selection acting on nucleotide variants and estimating the quence,
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